This competitive renewal application leverages our knowledge of kidney development to develop new strategies for addressing unmet needs in clinical nephrology. The lab has discovered critical genes and pathways that determine renal epithelial cell differentiation, growth, and survival. Many of these same pathways are important for renal cell regeneration and are deregulated in renal disease. During previous funding periods, we have made significant breakthroughs in defining the mechanisms of Pax2 protein function in development and disease. Pax2 is essential for specifying renal epithelial cells in development, is repressed in adult nephrons, but is reactivated in regenerating proximal tubules after injury. Our first aim will identify key targets of Pax2 regulation in development and in regenerating kidneys. We will test the interactions of Pax2 with epigenetic complexes and determine the function of Pax2 in regenerating tubules. The second aim capitalizes on our knowledge of Pax2 mediated gene regulation to identify small molecules that can attenuate Pax2 dependent gene expression. We have developed assays that can identify both enhancers and inhibitors of Pax2 function. Unbiased high throughput screens will be carried out to identify hits that modify Pax2 activity. Such hits can be fully characterized at the biochemical level, usin our established models of Pax2 function. Furthermore, computational methods based on homology modeling will be used to identify small molecule inhibitors for Pax2. Such inhibitors could be the basis for novel therapies against polycystic kidney disease or renal cell cancers in which high levels of Pax2 expression persist.